Vaso-occlusive phenomena and hemolytic anemia are the clinical hallmarks of sickle cell disease (SCD). Sickle (homozygous hemoglobin S, SS) red blood cell (RBC)-based adhesion and vaso-occlusive events likely initiate and/or exacerbate the profound vasculopathy present in SCD.1, 2 SS RBCs possess unusually active signaling pathways that contribute to a panoply of abnormalities, including RBC adhesion to the endothelium and vaso-occlusion.2-4 Vaso-occlusion results in recurrent painful episodes and a variety of serious organ system complications that can lead to life-long disabilities and even death.
Cell adhesion is a multistep cellular process that is regulated by complex extracellular and intracellular signals, which may differ from one cell type to another. We have previously shown that abnormal SS RBC interaction with the endothelium and with leukocytes can be increased via stimulation of β2 adrenergic receptors (ARs) by the stress hormone epinephrine.4-6 Such stimulation activates the intracellular cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway.4 βARs are prototypic G protein-coupled receptors (GPCRs), whose signaling properties are largely mediated by activation of stimulatory GTP-binding proteins (Gs proteins), which in turn activate adenylate cyclase (AC), leading to generation of cAMP, and the subsequent activation of PKA. The cAMP/PKA pathway can modulate the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERKs) cascade.7 PKA has been reported to stimulate B-Raf, while inhibiting c-Raf. Therefore, the activity of downstream signaling proteins, such as MEKs and ERKs, could be either enhanced or inhibited depending on the balance of c-Raf and B-Raf activation.8, 9 The cellular functions mediated by βARs can also be independent of adenylyl cyclase activation and involve other mediators instead.10, 11 
We recently demonstrated that MEK/ERK inhibitors are capable of alleviating the symptoms associated with hemoglobinopathy in subjects afflicted therewith. It would be advantageous to target further potential pathways and uncover further inhibitors to treat or block these symptoms.